The field of the invention is cellular receptors for viruses of the family Hepadnaviridae, and nucleic acids encoding the same.
The human hepatitis B virus (HBV) and related animal viruses that infect woodchucks, ground squirrels, Pekin ducks, and herons form a group of hepatotropic DNA viruses in the family Hepadnaviridae. In humans, HBV causes acute and chronic liver disease and hepatocellular carcinoma.
The initial event of infection, interaction between the viral envelope protein and specific cellular receptor(s), is poorly understood. Hepadnaviruses express at least two co-terminal envelope proteins from a single envelope gene by alternative use of in-frame AUG codons. The large envelope protein (pre-S/S protein) of duck hepatitis B virus (DHBV) contains a 161-163 amino acid segment called the pre-S domain, and a carboxylterminal 167 amino acid segment called the S domain. The small envelope protein (S protein alone) is produced by translation from an internal AUG codon. The large envelope protein of HBV is similar, but has pre-S1 and pre-S2 domains in place of the single DHBV pre-S domain. As a result, two pre-S containing proteins are produced: a large envelope protein (preS1+preS2+S) and a middle envelope protein (preS2+S). The large envelope protein is myristylated and phosphorylated (Grgacic et al., J. Virol. 68:7344-7350, 1994; Macrae et al., Virology 181:359-363, 1991; Persing et al., J. Virol. 61:1672-1677, 1987). The large envelope protein mediates infection by DHBV and by hepatitis delta virus (HDV), which borrows the envelope proteins of other hepadnaviruses to enter a hepatocyte (Fernholz et al., Virology 197:64-73, 1993; Summers et al., J. Virol. 65:1310-1317, 1991; Sureau et al., J. Virol. 67:366-372). The pre-S domain is believed to be responsible for binding a cellular receptor. Although several cellular proteins bind the HBV envelope, none have been shown to be the actual receptor (Budkowska et al., J. Virol. 67:4316-4322, 1993; Budkowska et al., J. Virol. 69:840-848, 1995; Hertogs et al., Virology 197:549-557, 1993; Mehdi et al., J. Virol. 68:2415-2424, 1994; Neurath et al., J. Exp. Med. 176:1561-1569, 1992; Pontisso et al., J. Gen. Virol. 73:2041-2045, 1992).
Since no cell culture system is available for the study of HBV, DHBV was developed as a model system. DHBV infection of ducklings and primary duck hepatocytes has been well characterized (Pugh et al., Virology 172:564-572, 1989; Tuttleman et al., J. Virol. 58:17-25, 1986).